For many pharmaceutically active compounds it is still preferred to have them orally administered by way of tablets. It is also well known that depending on how a pharmaceutically active ingredient is formulated into a tablet its release pattern can be modified. In this regard, tablets providing a retarded release profile are of primary importance. With retarded release tablets care has to be taken that under no circumstances the pharmaceutically active ingredient will be released completely and instantaneously in an uncontrolled manner (“dose-dumping”) since regularly the dosage used for retarded release tablets is much higher than for non-retarded release tablets. This may cause serious adverse effects or even death depending on the active ingredient and potency thereof.
Controlled release (e.g. delayed release, prolonged release, sustained release, and the like) may be based upon various concepts such as coating the pharmaceutical dosage form with a controlled release membrane, embedding the pharmacologically active compound in a matrix, binding the pharmacologically active compound to an ion-exchange resin, forming a complex of the pharmacologically active compound, and the like. In this context it can be referred to, e.g., W. A. Ritschel, Die Tablette, 2. Auflage, Editio Cantor Verlag Aulendorf, 2002.
In WO 01/97783 A1 a controlled-release, in particular a retarded release oral drug dosage form for releasing a drug into at least a portion of a region defined by the stomach and the front gastrointestinal tract is obtained by employing a solid monolithic matrix having a non-circular shape wherein the longitudinal axis has a maximum length of 3.0 cm and the transversal axis achieves a minimum length of 1.2 cm within one hour of immersion in water. Furthermore, it is required that the matrix has a shape which when projected onto a plane is either an oval or a parallelogram.
U.S. Pat. No. 4,353,887 discloses a divisible tablet which exhibits controlled and delayed release of an active substance. This is achieved by use of a coating on a compacted tablet having an oblong shape in which the ratio of length to width to depth is approximately 2.5 to 5:approximately 0.9 to 2:1 and the width constitute at most ⅔ of the length. In addition, one or more relatively deep dividing grooves have to be present which run perpendicular to the length and depth and have a total depth of from approximately ⅓ to approximately ½ of the depth of the tablet.
WO 01/08661 is directed to a controlled release formulation, capable of providing sustained, prolonged, repeat and/or delayed release of oxycodone.
WO 03/094812 relates to abuse-resistant opioid-containing solid dosage pharmaceuticals comprising a sustained release carrier and an analgesically effective amount of an opioid analgesic in combination with an opioid euphoria-inhibiting amount of an isolated nontoxic N-methyl-D-aspartate receptor antagonist which is substantially not released when the dosage form is administered intact.
WO 99/48481 discloses a tablet for the controlled release of an active pharmaceutical ingredient. The tablet comprises a core having a donut-like configuration with a cylindrical hole extending through the center of the core. The core is coated with a hydrophobic, water-insoluble material covering all of the core except that which is defined by the cylindrical hole.
GB-A 2 057 878 discloses a divisible tablet having controlled and delayed release of the active substance, consisting of a compact that is formed by at least one active substance in an adjunct composition that effects a delayed and controlled release of the active substance, the compact being of an oblong shape in which the ratio of length to width to depth is approximately 2.5 to 5:approximately 0.9 to 2:1 and the width constitutes at most ⅔ of the length, and in which one or more relatively deep dividing grooves are present which run perpendicularly to the length and depth and have a total depth of from approximately 113 to approximately '12 of the depth of the tablet, but are at least so deep that one fracture surface area multiplied by the number of possible fragments constitutes a maximum of 15% of the surface area of the undivided tablet, the base and top faces independently of one another are planar or are convexly curved about the longitudinal axis or about parallels to this axis, the side faces are planar, the end faces can be of any shape and edges are optionally bevelled or rounded.
DE-A 198 56 147 discloses a solid, elongate dosage form with a long axis and with a length which is defined by projection of the ends of the dosage form onto the long axis, where a cross-sectional area oriented perpendicular to the long axis has an area which is variable along the long axis and increases from a cross-sectional area which is located between the ends and has a minimal area essentially continuously toward the two ends up to in each case a cross-sectional area with a maximal area, wherein the distance of the maximal cross-sectional area which is located near one end from the maximal cross-sectional area which is located near the other end is, projected on the long axis, more than half the length of the dosage form.
DE 28 08 505 C2 discloses a tablet which dissolves at essentially constant speed and which contains a water soluble component as well as a water insoluble coating. It is required that the side of the tablet has to comprise one or more cavities having a breadth of 0.1 to 1.0 mm, a depth of 0.1 to 0.4 mm and a length of more than 0.1 mm, wherein the side of said cavities is less than ⅙ of the total side of the tablet.
In DE 692 29 881 T2 it is proposed to obtain a tablet having a retarded release profile by use of a water soluble gel as well as of a specific coating having a specific thickness. The coating has to contain either ethylcellulose or acetylcellulose and has to be water insoluble as well as insoluble in gastric liquids.
A tablet having a controlled release profile will according to WO 99/48481 A1 be obtained by use of a doughnut-shaped core material with a cylindrical hole. A hydrophobic, water-insoluble coating is applied to the doughnut-shaped core except for the side of said core which surrounds the cylindrical hole. In such a manner an inherent limitation of compressed monolithic tablets for extended release dosages shall be overcome, namely the increase in diffusion length resistance over time due to the insolubility of the polymer. Apparently, this problem has been solved by insuring that the inner exposed area of the doughnut-shaped configuration is clear of any coating.
In DE 42 39 085 A1 it is described to make use of an oblong tablet only the opposed edges of which are in contact with an underlying side but not the intermediate section. In this manner the tablet is easily divisible by use of one hand only. The two parts forming such an oblong tablet may have the form of spherical sectors.
It is well known that a pharmaceutical formulation or its mode of manufacture, e.g. for an oral dosage form, might undergo modifications during clinical testing, for example with respect to the ingredients used or to the relative amounts of the excipients, or with respect to the reaction conditions and reactants used during manufacture. Frequently, such modifications at least to some extent have an impact on the release profile of pharmaceutically active ingredients. This is particularly unpleasant if for a specific formulation an approved optimized release profile has already been found which can not be reproduced with the modified formulation. In such a case, the clinical tests have either to be interrupted or have to be started from the beginning. Given the huge expenditures necessary to bring a new drug formulation up to and through clinical testing the above scenario has indeed proven to be rather unsatisfactory.
Pharmaceutical dosage forms having an increased breaking strength (resistance to crushing) have been recently reported. Dosage forms of this type may also exhibit a certain degree of controlled release of the pharmacologically active compound contained therein. The major advantage of such pharmaceutical dosage forms is that comminuting, particularly pulverization, by conventional means, such as grinding in a mortar or fracturing by means of a hammer, is impossible or at least substantially impeded.
On the one hand, pharmaceutical dosage forms having an increased breaking strength are useful for avoiding drug abuse of the pharmacologically active compound contained therein. Many pharmaceutical active compounds, in addition to having excellent activity in their appropriate application, also have abuse potential, i.e., they can be used by an abuser to bring about effects other than those intended. Opiates, for example, which are highly active in combating severe to very severe pain, are frequently used by abusers to induce a state of narcosis or euphoria. In order to make abuse possible, the corresponding pharmaceutical dosage forms, such as tablets or capsules are comminuted, for example ground in a mortar, by the abuser, the active compound is extracted from the resultant powder using a preferably aqueous liquid and the resultant solution, optionally after being filtered through cotton wool or cellulose wadding, and is administered parenterally, in particular intravenously. An additional phenomenon of this kind of administration, in comparison with abusive oral administration, is a further accelerated increase in active compound levels giving the abuser the desired effect, namely the “kick” or “rush”. This kick is also obtained if the powdered pharmaceutical dosage form is administered nasally, i.e. is sniffed. Since controlled-release pharmaceutical dosage forms containing active compounds with abuse potential do not give rise to the kick desired by the abuser when taken orally even in abusively high quantities, such pharmaceutical dosage forms are also comminuted and extracted in order to be abused. Pharmaceutical dosage forms exhibiting an increased breaking strength, however, may not be powdered by conventional means and thus, cannot be administered nasally thereby avoiding drug abuse. In the context of such tamper resistant dosage forms, it can be referred to, e.g., WO 2005/016313, WO 2005/016314, WO 2005/063214, WO 2005/102286, WO 2006/002883, WO 2006/002884, WO 2006/002886, and WO 2006/082097.
These dosage forms have a breaking strength of at least 500 N in every direction of extension.
On the other hand, pharmaceutical dosage forms having an increased breaking strength are useful for avoiding an (unintentional) overdose of the pharmacologically active compound contained therein, which overdose would otherwise be caused by diminishing the retardant effect due to pulverization. It is known that many patients, particularly older patients frequently have difficulties in taking solid pharmaceutical dosage forms, such as tablets, gelatine capsules, etc. They choke on them and sometimes develop pronounced aversion to such pharmaceutical dosage forms. To counter this problem, various apparatuses have been developed by means of which conventional solid pharmaceutical dosage forms may be comminuted or pulverized (“tablet crushers”). Such apparatuses are used, for example, by the care staff in old people's homes. The pharmaceutical dosage forms are then administered to the people being cared for not as tablets etc. but rather as powder, for example to get round the difficulties involved in swallowing tablets. However, the comminution of pharmaceutical dosage forms with such apparatuses is problematic if the pharmaceutical dosage forms are prolonged-release formulations. As a rule, comminution results in destruction of the inner structure of the pharmaceutical dosage form, which is responsible for the prolonged release, so doing away with the prolonged-release action. Consequently, after administration, frequently all the physiologically active substance originally contained in the pharmaceutical dosage form is released in a relatively short time, whereby a comparatively very high plasma concentration of the substance is abruptly reached within a relatively short time frame. In this way, the originally prolonged-release formulations become immediate release formulations. Depending on the physiological activity of the substance, this may cause considerable side-effects however, and in extreme cases may even lead to the death of the patient. Pharmaceutical dosage forms having an increased breaking strength, however, cannot be comminuted by tablet crushers and thus, have to be swallowed as a whole thereby avoiding any (unintentional) overdose. In this context, it can be further referred to, e.g., WO 2006/082099.
These dosage forms also have a breaking strength of at least 500 N in every direction of extension.
The release profile of controlled-release formulations depends on a variety of factors, such as properties of the pharmaceutical dosage form per se, nature and content of the matrix, nature of the release medium, nature and content of the active compound, nature and content of further pharmaceutical excipients as well as the interrelationship of these factors. When the control of the release profile relies on a polymer matrix in which the active compound is embedded, the release rate depends on the properties of the pharmaceutical dosage form as such, e.g. its geometry, method of manufacture, additives and excipients contained therein, and the like. Further, the release rate depends on the properties of the matrix polymer, such as molecular weight, viscosity, particle properties, interaction with other polymers, chain entanglements, degree of cross-linking, chemical nature of monomer units, interaction of the matrix material with the release medium (e.g., swelling and gelling), and the like. Still further, the release rate depends on the properties of the active compound, e.g., its dose, particle size, particle form and its solubility in the release medium, which in turn is a function of various properties, such as molecular size, molecular weight, ionogenicity, acidity, steric hindrance, arrangement of dipols, hydrophilicity, etc. Furthermore, the release rate depends on the individual interactions of a given matrix material with a given active compound (cf. Ning Wu et al., Journal of Controlled Release 102 (2005) 569-81; V. S. Manthena et al., Am J Drug Deliv. 2004 2(1) 43-57).
The release profile of conventional pharmaceutical dosage forms that do not exhibit an increased breaking strength can usually be adjusted within certain limits, usually by the variation of the content and/or the nature of the pharmaceutical excipients, such as the matrix forming polymer.
In some cases it has also been reported that the release of a drug in the body can be controlled by the surface area to volume ratio of a conventional dosage form which does not exhibit an increased breaking strength. For example, U.S. Pat. No. 5,427,798 discloses film coated tablets containing bupropion hydrochloride and having a surface area to tablet volume of 3:1 to 25:1 cm−1 for tablets of 50, 100 and 150 mg drug content. Similarly, U.S. Pat. No. 4,940,556 and U.S. Pat. No. 5,198,226 disclose spheroids containing dihydropyridine calcium channel blockers and having area radius to circumference radius ratios in the range of 0.85 to 1.0.
With respect of pharmaceutical dosage forms exhibiting an increased breaking strength, however, the variation of the content, the nature of the pharmaceutical excipients and/or the surface area to volume ratio also affects the mechanical properties. This is because the increased breaking strength of the pharmaceutical dosage form typically relies on the presence of a particular polymer that is processed by a particular method when manufacturing the pharmaceutical dosage form. It seems that said polymer also serves as a matrix embedding the pharmacologically active compound. In consequence, the polymer matrix that is essential to the breaking strength of the pharmaceutical dosage form simultaneously serves as a controlled release matrix and thus, varying the content, nature and/or spacial distribution of the polymer causes both, a change of the release profile as well as a change of the mechanical properties of the pharmaceutical dosage form.
Particular problems arise when the dose of the pharmacologically active compound and thus, also the total weight of the pharmaceutical dosage form is comparatively high. Depending upon the content and the nature of the pharmacologically active compound and of the pharmaceutical excipients, the retardant effect of the polymer may be so strong that the pharmaceutical dosage form cannot be adapted to a specific dosing regimen, e.g., twice daily, particularly when the increased breaking strength is to be maintained.
On the one hand, a decrease of the content of the retardant polymer for the purpose of accelerating drug release would substantially affect the mechanical properties of the pharmaceutical dosage form and in a worst case scenario, would completely diminish its specific and unique mechanical properties (breaking strength). Further, a decrease of the content of the matrix polymer beyond a certain limit may cause a deterioration or even loss of other desired properties, such as storage stability. A poor storage stability results, e.g., in a change of the release profile over time.
On the other hand, the addition of non-retardant pharmaceutical excipients (auxiliaries) for the purpose of weakening the retardant effect of the retardant polymer would increase the total weight of the dosage form. As highly dosed pharmaceutical dosage forms have comparatively high total weights anyway, a further increase of the total weight is disadvantageous and could deteriorate patient compliance (e.g. swallowability).
Thus, there is a demand for pharmaceutical dosage forms, particularly tamper-resistant pharmaceutical dosage forms, the release profile of which may be varied within certain limits without diminishing the tamper resistance and without deteriorating the compliance of the pharmaceutical dosage form.
It, thus, has been an object of the present invention to provide an oral dosage form which does not exhibit the shortcomings of the dosage forms of the state of the art and which in particular allows for an improved control of the release profile of the active pharmaceutical ingredient incorporated in the oral dosage form. It has been another object of the present invention to be able to regain the original release profile of an elaborated formulation for an oral dosage form, the release pattern of which has experienced changes due to modifications to the composition of said formulation.
This object has been solved by the subject-matter described hereinbelow.